This invention relates to a process for treating Parkinson's Disease and to compositions useful in such treatment.
There are presently several dopaminergic drugs either in use or being considered for use in the treatment of Parkinson's Disease, including L-DOPA, several ergot alkaloids, apomorphine derivatives and substituted 2-aminotetralins, as well as some N-substituted dopamine analogs. In one way or another, all of these compounds are based on the structure of dopamine, and most, if not all, contain the dopamine skeleton in its presumed active conformation. Based upon these rigid and semirigid agonists, as well as the structures of some confirmed dopamine antagonists, the active conformation of dopamine is now generally agreed upon. One question remaining is the exact effect of the phenyl ring hydroxyl groups. Although recent results seem to indicate that the so-called .alpha.-rotamer is the more active, others indicate that the .beta.-rotamer also possesses activity, but in the opposite configuration. It is not yet clear if these activities are at different sites or receptors. In either case, all the drugs developed to date suffer from one or more potential clinical disadvantages, including poor absorption, inability to gain access to the central nervous system, rapid metabolic degradation, serious side effects and high toxicity.
Although the primary etiology of Parkinson's Disease remains unknown, substantial effort over two decades has produced a solid framework of knowledge regarding the processes that occur during its course. This improved state of understanding is based on advances in neurology, neurochemistry and neuropharmacology, and the resulting rational therapeutic improvements and new leads have followed from these advances.
Parkinson's Disease is now known to be based on a neurochemical defect in the nigrostriatal dopaminergic pathways of the basal ganglia, in which the dopaminergic neurons suffer severe degenerative changes. One of the consequences of these changes is the creation of a functional imbalance between the stimulatory cholinergic system and the inhibitory dopaminergic system along with changes in other subsystems, e.g., GABA. These result in the clinical symptoms of tremor, akinesia and rigidity. Even before the clinical symptoms appear, several neurochemical changes occur. As the dopaminergic neurons begin to degenerate, the activity of the remaining neurons elevates to compensate for the loss. This process is apparently mediated by several feedback mechanisms, including presynaptic and dendritic dopamine receptors (autoreceptors), the stimulation of which produces an inhibitory response in the dopaminergic neuron. This degeneration-increased activation process continues until neurohumoral balance cannot be maintained, and decomposition occurs. Along with this increased activity, postsynaptic dopamine receptor supersensitivity also develops, perhaps by way of increased receptor density. This postsynaptic adaptation likely serves to utilize the limited dopamine more effectively; it may also provide greater therapeutic access by way of an increased responsiveness to exogenous drugs directed to the postsynaptic receptor.
It has been clear for some time that dopamine receptors exist in different forms, as well as different locations in both the central nervous system and the periphery. A distinction has been made between those dopamine receptors that activate adenylylcyclase when stimulated (D1) and those that do not (D2 receptors). Both receptor types exist in more than one location, and subpopulations of each can be distinguished on the basis of their differential responses to selected agonists and antagonists. Not all of these subpopulations are relevant to Parkinson's Disease, which is known to be centered in the nigrostriatal axis. In this axis, at least five dopamine binding sites have been identified. These include a presynaptic D1 receptor intrinsic to the caudate nucleus that appears not to perform a major autoregulatory function, and a postsynaptic D1 receptor that projects to the substantia nigra. The D2 receptors include presynaptic autoreceptors that regulate dopamine neuronal activity as well as ones that affect tyrosine hydroxylase activity. The fifth receptor is a postsynaptic D2 receptor whose function is neurochemically less well described but may be that of a classic dopamine receptor. Not enough information is available to precisely define the entire process of motor regulation and the role each receptor plays. It has been proposed that Parkinson's Disease results from diminished stimulation of the postsynaptic D2 receptor, with the decompensated state arising when the autoreceptors can no longer maintain equilibrium in the systems. Therapeutic access to Parkinsonism then becomes a function of either the replacement of dopamine at the striatal (presumably D2) receptor or suitable stimulation of the receptor with some other synthetic drug. It has been suggested that the ideal agent for Parkinson's Disease should (a) have direct, full agonist action on postsynaptic dopamine receptors, (b) have transport characteristic suitable for easy access to the central nervous system (especially striatum) and (c) be metabolically stable, long lasting and with no adverse side effects. Unfortunately, such a drug does not yet exist.
However, several partial successes in the achievement of this goal have occurred, the first fully rational one being the use of L-DOPA to restore dopamine levels in the striatum. Although dopamine itself is not effectively transported into the central nervous system, its direct precursor amino acid, L-DOPA, is enzymatically decarboxylated after its facilitated central nervous system transport and uptake into the intact dopaminergic neuron and possibly other non-dopaminergic neurons. The dopamine is subsequently released into the synaptic cleft. While L-DOPA was originally expected to offer complete control of Parkinson's Disease symptoms, it is now apparent that it has serious shortcomings, including side effects. Some of these are due to the high levels of dopamine from peripheral decarboxylation of L-DOPA, while other effects are not fully explainable (dyskinesias, "on-off" syndrome). More importantly, L-DOPA becomes ineffective as the disease progresses, since it depends upon intact dopaminergic neurons for its uptake and activation. In this sense, L-DOPA acts indirectly through the intact neurons rather than directly at the postsynaptic dopamine receptor. In terms of the above ideal attributes, it is a less than ideal drug in all three areas.
Other drugs have promise as well. As a class, the ergots have been well investigated and some have reached clinical use, including bromocriptine and pergolide. These compounds appear to have mixed actions at therapeutic levels for both D1 and D2 sites. Despite some clinical success, the ergots suffer from disadvantages in several areas as antiparkinson drugs, including serious side effects caused by interactions with other (e.g., noradrenergic, serotonergic) neurotransmitter systems, low therapeutic index, and high cost. Thus, they meet only the first two of the above criteria of ideality.
Apomorphine and its derivatives have also been carefully studied, both as pharmacological tools and as potential antiparkinson drugs. The compounds are rigid congeners of dopamine and they have been shown to be both partial D1 agonists and potent D2 agonists which effectively reverse clinical Parkinsonian symptoms, although not as effectively as L-DOPA. Apomorphine is not a clinically useful drug, however, due to its short duration of action, poor oral absorption, side effects (nausea, nephrotoxicity) and metabolic instability. While congeners of apomorphine such as N-n-propyl norapomorphine seem to be therapeutically more promising, at the present time the troublesome side effects and instabilities remain.
A series currently receiving considerable attention is the catecholic 2-amino-tetralin class, or ADTN (2-aminodihydroxytetrahydronaphthalene). The 5,6- and 6,7-dihydroxy isomers (1 and 2, respectively) are semirigid congeners of dopamine in the extended conformation. Considerable insight into the receptor conformation of dopamine has come from these compounds as well as apomorphine, although it is not fully clear what the roles of the two phenyl ##STR1## rotameric forms (.alpha. and .beta.) are. Both 1 and 2 are dopamine agonists, with 2 being generally somewhat more potent than 1. However, the observed potencies of 1 and 2 are highly dependent on the test system used. Apparently, no clinical experience has been obtained with 1 or 2, but in animals a major drawback is an inaccessibility to the central nervous system. It is also not yet clear whether some degree of dopamine selectivity may result from restriction of rotation. The central nervous system shortcoming may be overcome by some of the more recently synthesized tertiary derivatives and prodrugs, with which side effects and metabolic stabilities may be more easily examined. In short, the ADTN series has the necessary direct dopamine agonist property, but the second and third of the above criteria await further evaluation.
While several other agents have been investigated (e.g., piribedil, a metabolically activated direct agonist, and deprenil, a selective MAO-B inhibitor), much work must be done to find agents without the troublesome side effects, metabolic instabilities and transport problems presently associated with the known direct agonists.
One clinically useful antiparkinson drug that has a nearly ideal pharmacokinetic and metabolic profile and is virtually free of side effects, is amantadine (1-aminoadamantane)3. Unfortunately, amantadine has no direct dopamine agonist activity of its own. While its exact mechanism of action is unclear, it appears to exert its weak effect indirectly by facilitating release of dopamine or hindering its uptake. The compound 3,5-dimethyl-1-aminoadamantane also exhibits antiparkinson activity but also has no direct agonist activity of its own. If one or more congeners of amantadine could be developed that has a significant direct dopamine agonist component, it would likely approach all three of the above criteria for an ideal antiparkinson drug, and hold great promise for clinical control of Parkinsonian symptoms.